Gestational Vitamin D Supplementation Leads to Reduced Perinatal RXRA DNA Methylation: Results From the MAVIDOS Trial.
Gestational Vitamin D Supplementation Leads to Reduced Perinatal RXRA DNA Methylation: Results From the MAVIDOS Trial.
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DOI：
10.1002/jbmr.3603
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
MAVIDOS Trial Group
中科院分区：
文献类型：
--
作者：
Curtis EM;Krstic N;Cook E;D'Angelo S;Crozier SR;Moon RJ;Murray R;Garratt E;Costello P;Cleal J;Ashley B;Bishop NJ;Kennedy S;Papageorghiou AT;Schoenmakers I;Fraser R;Gandhi SV;Prentice A;Javaid MK;Inskip HM;Godfrey KM;Bell CG;Lillycrop KA;Cooper C;Harvey NC;MAVIDOS Trial Group
我们之前已经证明了母体25（OH）-维生素D状态与围产期类维生素A-X-受体-α（RXRA）基因座DNA甲基化之间以及RXRA甲基化与后代骨量之间的负相关性。在这项研究中，我们使用了一个现有的随机试验来检验这一假设，即母亲妊娠期补充维生素D会导致围产期RXRA基因座DNA甲基化减少。母体维生素D骨质疏松症研究（MAVIDOS）是一项多中心、双盲、随机、安慰剂对照试验，从妊娠14周至分娩期间给予1000 IU/天胆钙化醇或匹配安慰剂。脐带（胎儿）组织在出生时收集并在-80 °C下冷冻（n = 453）。焦磷酸测序用于在RXRA基因座内的10个CpG位点（先前鉴定）进行DNA甲基化分析。使用T检验来评估治疗组之间在三个最具代表性的CpG位点的甲基化的差异。总体而言，补充胆钙化醇的母亲的后代的脐带中甲基化水平显著较低，在4个CpG位点达到统计学显著性，以CpG 5为代表：补充组和安慰剂组之间甲基化%的平均差异为−1.98%（95% CI，−3.65至−0.32，p = 0.02）。ENCODE（DNA元件百科全书）证据支持该基因座在生物学相关细胞类型（包括成骨细胞）中具有强DNA酶超敏性和增强子染色质的功能。增强子相关的H3 K4 me 1组蛋白标记的富集也见于该区域，作为一系列转录因子的结合位点，其在细胞增殖、应激反应和生长因子中发挥作用。我们的研究结果与以前的观察结果一致，并提供了新的证据表明，母亲妊娠期补充胆钙化醇会导致围产期表观遗传标记的改变，为与母亲维生素D状态，表观遗传标记和骨骼发育相关的早期生命机制的机械理解提供了信息。版权所有© 2018作者.骨与矿物质研究杂志由Wiley Periodicals Inc.出版。
We have previously demonstrated inverse associations between maternal 25(OH)‐vitamin D status and perinatal DNA methylation at the retinoid‐X‐receptor‐alpha (RXRA) locus and between RXRA methylation and offspring bone mass. In this study, we used an existing randomized trial to test the hypothesis that maternal gestational vitamin D supplementation would lead to reduced perinatal RXRA locus DNA methylation. The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicenter, double‐blind, randomized, placebo‐controlled trial of 1000 IU/day cholecalciferol or matched placebo from 14 weeks’ gestation until delivery. Umbilical cord (fetal) tissue was collected at birth and frozen at −80°C (n = 453). Pyrosequencing was used to undertake DNA methylation analysis at 10 CpG sites within the RXRA locus (identified previously). T tests were used to assess differences between treatment groups in methylation at the three most representative CpG sites. Overall, methylation levels were significantly lower in the umbilical cord from offspring of cholecalciferol‐supplemented mothers, reaching statistical significance at four CpG sites, represented by CpG5: mean difference in % methylation between the supplemented and placebo groups was −1.98% (95% CI, −3.65 to −0.32, p = 0.02). ENCODE (Encyclopedia of DNA Elements) evidence supports the functionality of this locus with strong DNase hypersensitivity and enhancer chromatin within biologically relevant cell types including osteoblasts. Enrichment of the enhancer‐related H3K4me1 histone mark is also seen in this region, as are binding sites for a range of transcription factors with roles in cell proliferation, response to stress, and growth factors. Our findings are consistent with previous observational results and provide new evidence that maternal gestational supplementation with cholecalciferol leads to altered perinatal epigenetic marking, informing mechanistic understanding of early life mechanisms related to maternal vitamin D status, epigenetic marks, and bone development. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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影响因子：
4.1
作者：
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通讯作者：
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DOI：
10.1016/j.jsbmb.2016.03.005
发表时间：
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影响因子：
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作者：
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